4. A 71-year-old male, failed kidney transplant 15 years ago had a kidney from his daughter. The HLA mismatch is 110, FCXM is negative. There is a history of 7 BCC and 2 early SCC, which were excised and completely treated.
- What immunosuppression protocol should be used?
- What is your prophylactic approach against his skin cancer?
- Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
Based on pt has negative cross match and good HLA matching but with 2nd kidney transplantation)+BCC and SCC :
So I will go for Basiliximab ,and methyleprednisone ,,maintainance :tacrolimus +MMf +prednisone in the 1st 3months and after that I will change to sirolimus after that .
Prophylactic approach to avoid sun exposure and dermatology follow up .,use of sirolimus as maintenance ,and not using Thymoglobulin in induction and to use tacrolimus as maintenance only early in transplantation.
Yes I will not go to transplantation as this has high immunological risk and patient BCC and SCC will recur if more potent ind uction and maintenance IS medications were used (Thymoglobulin and tacrolimus)
1- What immunosuppression protocol should be used?
2- What is your prophylactic approach against his skin cancer?
3- Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
induction Basiliximab, being low to moderate risk
Maintenance IS: sirolimus, MMF& steroids.
Based on : previous Tx , only 2 mismatches with negative FCXM ;so induction with Basiliximab
Sirolimus is preferred due to anti-tumor effects, and avoidance of cyclosporine , azathioprine due to his history of skin cancer
Avoidance of sun exposure and use sunscreen
Full body coverage: long-sleeved shirts and pants with dark colored, tightly woven material to give the most UV protection. Also, wearing sunglasses and using hat.
Frequent dermatology checks for screening.
High risk , but yet without changing the protocol
It is better to decline the donor , otherwise although induction with ATG is needed I may still go with Basiliximab considering cost-benefit considering history of skin cancer, age of 71years (immunsenescence with aging );not favoring aggressive approach.
In view of age and previous malignancy history and a decent degree of HLA match
I would use Basiliximab induction to avoid malignancy risk. I will avoid CYC as it is
known to promote the development of TGF beta and enhances tumor
progression. There are lot of trials on the reduction of de novo malignancies after
CNI withdrawal. MMF has known to have anti proliferative actions and I will
continue it post transplant period. I will switch over to sirolimus or everolimus after
3months if the eGFR>30ml/min and there is urine protein creatinine ratio is less
500mg/24 hours.
Low to moderate risk : induction Basiliximab
Mentainence IS: asteroids, sirolimus, MMF
Rationale: patient has had a previous Tx , yet only 2 mismatches with –ve FCMXM hence Induction with Basiliximab
Sirolimus is preferred due to anti cancer effects, avoid cyclosporins , azathioprin in this patient due to his history of skin cancer
Avoid sun exposure, use sunscreen
Full body coverage: long-sleeved shirts and pants. Dark coloured, tightly woven material provides the most UV protection.
Wear sunglasses , use a hat
Frequent dermatologist visits for screening and early detection
High risk , yet I may not change the protocol
I may prefer to decline the donor , otherwise although induction with ATG is needed I may still go with Basiliximab considering cost and benefits taking in consideration the history of skin cancer , patients age is 71 , elderly develop immunsenescence with aging . so why the use of aggressive IS.
1- Due to having history skin cancer , I would choose mTOR + MMF + steroid as immunosupression.
2- CNIs would increase risk of recurrent skin malignancy.
1- Sun exposure reduction.
2- dermatological consultation pre-transplantation and periodic surveillance.
3- Use of sirolimus /everolimus would decrease risk of skin cancer.
4- Use of reduced doses of immunosuppressive medications.
Then it would be high risk donor
Induction: ATG
maintenance: mTOR inhibitor + steroid
Q1:
mTOR inhibitor based protocol and MMF and steroids with or without basiliximab induction is preferred.
Q2: The recipient should be aware of sun protection by using sunscreen daily with reasonable usage of vitamin D supplements.
Alteration in immunosuppressive protocol with an mTOR based one and mild reduction of immunosuppression due to 7SCC, chemoprevention with systematic retinoid such as acitrerin or isotretinoin, nicotinamide and capecitabine are good options.
Monitoring for skin-cancer post-transplantation should be done in regular intervals by a dermatologist at least every three months and by self-examination at least every month.
Q3: This donor is not the best option for this situation. I would prefer a more matched donor by KPD. If not possible, desensitize the patient and use a CNI inhibitor + mTOR inhibitor + prednisolone protocol in addition to induction therapy.
What immunosuppression protocol should be used?
Cyclosporine has been shown to cause resistance to UV-induced apoptosis in human keratinocytes. And also promote tumour growth and invasion by inducing the production of growth factors, such as TGF-which augment epithelial-to-mesenchymal transition and promote tumour progression. Whereas tacrolimus associated with a lower relative risk of skin cancer than cyclosporine
Azathioprine has been found to sensitize cells to UV-induced dam-age through the incorporation of a metabolite into DNA that generates reactive oxygen species on exposure to UV light and noted to have more frequent mutations in the gene encoding p53.
Mycophenolate mofetil has a lower relative risk of skin cancer, does not appear to have the muta-genic properties of azathioprine, potentially explaining the lower relative risk of skin cancer with this drug. The use of MMF leads to a decreased risk of SCC but an increased risk of BCC
Trials have demonstrated that conversion from a traditional immunosuppressive regimen,s pecifically calcineurin inhibitors to sirolimus, reduces the risk of keratinocyte carcinoma.
So, taking all this into account, we can have 2 regime of IS protocol,
1- low dose tacrolimus, MMF and steroids with or without mTOR
2-CNI avoidance regime; mTOR, MMF and steroids
What is your prophylactic approach against his skin cancer?
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
If there is no different potential donor, I would proceed with transplantation as it will be beneficial for survival, I would use low dose tacrolimus or mTOR with MPA.
This patient with History of skin malignancies is better to be maintained on mtor inhibitors rather than CNI,
As mtor Inhibitors reduces risk of skin malignancies 40 to 50 %
MMF are better than azathioprine regarding risk of skin malignancies
I would consider this offer as low immunological risk, I would use basiliximab as induction therapy
As a prophylaxis
Patient education of self examination, sun protection .
Pre transplant dermatology consultation for any suspicious lesion
lowest possible doses immunosuppressive
drugs, with the use of mtor inhibitors rather than CNIs
Chemoprevention is indicated in certain situations ( aggressive SCC , recurrent > 5 times / year )
Finally post transplant surveillance.
all would reduce risk of post transplant skin malignancies
Up-to-date 2021
An offer of 212 mismatch
DSA 1500 MFI , against HLA B
Negative FCXM
Some studies related degree of mismatch to incidence of skin malignancies
The high degree of mismatch would let me use an induction agent as thymoglobulin,
No desensitization is needed as MFI is only 1500
I would use with low dose CNI together with mtor inhibitors, MMF and steroids .
Then gradually tapper CNIs till I stop them if possible
What immunosuppression protocol should be used?
Immunological risk: old age 71 year, Previous RTx 15 years ago, Donor MM 110, negative FCXM——àlow risk Tx offer, However, history of skin cancer, being old age make him liable to develop recurrence of malignancy.
IS protocol:
Induction: Basiliximab (non-depleting agent).
Maintenance: mTORi (Sirolimus)+ MMF+ prednisolone.
CNIs, Azathioprine increase the risk of non-melanoma skin cancer.
mTOR inhibitors, MMF may reduce the risk of nonmelanoma skin cancer.
new protocols (use Belatacept or steroid free regimen) showed long term beneficial effect on tumor recurrence, can hopefully be used in the future.
What is your prophylactic approach against his skin cancer?
Prophylactic approach against skin cancer includes the following:
1- Use of Sun Screen protection.
2- Pre-transplant skin screening by dermatologist.
3- Self-examination at least monthly by the patient annually by dermatologist.
4- Patients with previous BCC or low risk SCC don’t require waiting time before Tx.
5- Patients with previous high-risk SCC require waiting time for 2-3 years.
6- Patients with SCC with local LN extension should wait for 5 years after being treated.
7- Patients with distant metastasis are excluded from transplantation.
8- Reduction of immunosuppression is most beneficial with Kaposi sarcoma, however its benefit is not clear in melanoma, BCC, and SCC.
9- Use of Sirolimus and MMF (instead of CNIs and Azathioprine) is associated with reduction of malignancy including skin cancer.
10-Avoid voriconazole as prophylaxis and treatment of invasive fungal infections.
11-For SCC prevention: systemic retinoids, nicotinamide, capecitabine were used in the studies as chemo preventive agents and were effective, photodynamic therapy as a protective measure to SCC was studied and the results were mixed.
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
If MM 212 with DSA against B51 with MFI 1500 with negative cross match will make the donor offer high immunological risk which require:
Induction IS options: with low dose ATG vs Alemtuzumab (less influence on increasing malignancy) vs Basiliximab (increased risk of graft loss in high immunological risk).
I will opt for ATG because it is high immunological offer.
Maintenance: CNIs+ MMF+ Steroids then 3-6 months later–àSirolimus/everolimus +MMF+ steroids
Follow up: DSA, dermatologist, protocol biopsy.
No need for desensitization as cross match is negative.
References:
●●What immunosuppression protocol should be used?
induction
basiliximab
Maintenance
1-steroid
2-mTOR inhibitors — sirolimus or everolimus may reduce the risk for malignancies, including nonmelanoma skin cancer, in organ transplant recipients
3.mmf
●●What is your prophylactic approach against his skin cancer
Decrease steroids and maintenance immunosuppressive dose
1excision,
2photodynamic therapy and
3topical medicines such as the chemotherapy drug 5-fluorouracil or the immune-boosting therapy imiquimod, which can treat a broad area of skin that has many visible or invisible lesions
4 The oral retinoid acitretin can prevent SCC in transplant recipients, 5.nicotinamide (a variant of vitamin B3) may also be protective in patients who have already had SCC..
●●Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
Yes needs aggressive induction with ATG . Reference
https://www.skincancer.org/blog/after-a-transplant-new-dangers/
What immunosuppression protocol should be used?
IL2 inhibitor (basliximab) because he had low immunological risk
What is your prophylactic approach against his skin cancer?
CNI minimization protocol with mTOR inhibitors because they had anti malignancy effect
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
Yes the mangment will differ as he became high risk and may need induction with ATG and CNI plus mTOR and predinsilone
With meticulous follow up for recurrence of skin cancer
SCC and BCC consider around 90% of skin malignancy solid organ transplantation
risk of skin malignancy post transplant can be divided to 2 main groups
· factors related to transplant
1. immunosuppressive medications like CNI which interfer with DNA damage after UV exposure
2. duration of transplantation: risk increase after 6y in older recipient and after 12y in younger one
3. intensified immunosuppression : this is still no obvious correlation but it may caused by oncoviruses like HPV in such patients
· factors related to recipient
· age :more in older patients
· sex: male more than females
· ethnicity: white more than black
· sun exposure
Although matching is not that good but its living related donor and patient age is 70
I will proceed for renal transplantation by basilimab induction and triple tac/mmf/steroids and after 6m- 1y switching from CNI to mTOR (sirolimus) or low dose CNI +mTOR
(no clear data support that ATG induction increase risk for SCC and BCC but this old recipient basilixmab is just enough for him)
What immunosuppression protocol should
be used?
induction
basiliximab
Maintenance
1-steroid
2-mTOR inhibitors — Compared with calcineurin inhibitor-based regimens, immunosuppression with the mTOR inhibitors sirolimus or everolimus may reduce the risk for malignancies, including nonmelanoma skin cancer, in organ transplant recipients
3-Mycophenolate mofetil versus azathioprine — A few studies have shown that mycophenolate mofetil and mycophenolic acid are associated with a lower incidence of skin cancer in solid organ transplant recipients compared with azathioprine
4-Reduction of immunosuppressive therapy — Because increased intensity and duration of immunosuppression appear to promote the development of cutaneous malignancies in organ transplant recipients, reduction of immunosuppression may be considered in patients who develop numerous lesions, recurrent disease, or metastatic disease
• What is your prophylactic approach against his skin cancer?
PRETRANSPLANTATION SCREENING
A dermatologic consultation is recommended before transplantation for the screening and treatment of skin cancer and precursor lesions. All suspicious lesions should be excised and sent for pathologic examination. Actinic keratoses, porokeratoses, and viral warts should be treated. A careful history of previous skin cancer should also be obtained to determine the appropriate follow-up frequency or the wait time before proceeding to transplantation
Wait time — For patients with a history of prior cutaneous malignancy, the wait time before undergoing transplantation depends upon the tumor type and stage, presence or
absence of high-risk features, and availability of a management approach alternative to transplantation. Consensus-based recommendations from the International Transplant Skin Cancer Collaborative are summarized here
PREVENTION
●Patient education concerning sun protection and skin self-examination
●Choice and modulation of immunosuppressive therapy
●Chemoprevention
●Post-transplantation surveillance
• Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
negative FCXM ,positive DSA
NO need for desensitization
Induction with ATG without desensitization
Maintenance
1-steroid
2-mTOR inhibitors
3- Mycophenolate mofetil versus azathioprin
1. Moloney FJ, Comber H, O’Lorcain P, et al. A population-based study of skin cancer incidence and prevalence in renal transplant recipients. Br J Dermatol 2006; 154:498.
2. Kim C, Cheng J, Colegio OR. Cutaneous squamous cell carcinomas in solid organ transplant recipients: emerging strategies for surveillance, staging, and treatment. Semin Oncol 2016; 43:390.
3. Tufaro AP, Azoury SC, Crompton JG, et al. Rising incidence and aggressive nature of cutaneous malignancies after transplantation: An update on epidemiology, risk factors, management and surveillance. Surg Oncol 2015; 24:345.
4. Campbell SB, Walker R, Tai SS, et al. Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer. Am J Transplant
2012; 12:1146.
What immunosuppression protocol should be used?
Retransplantation entails a new load of immunosuppressive medications, including often a depleting induction treatment, and thereby increases the risk of new SCC.
data suggest that the risk could be reduced by a tailored immunosuppression.
Patient has 2 mismatchs with 0 mismatch at HLA-DR no DSA and FCXM IS negative
With history of skin cancer in previous transplantation
Induction with non depleting Antibodies as basiliximab
And mentinance on steroids,MMF as it has lower association with skin cancer
KTR with skin cancer better to be switched to mTOR inhibitors.
several studies have shown a decrease of skin cancers in KTR under sirolimus as compared with those receiving calcineurin
And its better to avoid use of azathioprine and T cell–depleting treatments after the second transplantation as they significantly associated with aggressive SCC after the second transplantation.
A wait period may be required depending on the clinicopathological characteristics of the previous SCC and discussed on an individual patient basis.
What is your prophylactic approach against his skin cancer?
stronger prevention measures should be applied, especially in patients who accumulate several risk factors of aggressive SCC. These measures include adequate education about strict sun protection use of sun block is recommended.and regular dermatologic monitoring for early ablation of (pre)malignant lesions with adequate safety margins.
With 212 mismatchs and low DSA and still negative FCXM
The patient is at high immunological risk so induction with alemtuzumab
and mentinance on steroids,MMF and sirolimus
Ducroux E, Martin C, Bavinck JN et al.Risk of aggressive skin cancers after kidney retransplantation in patients with previous posttransplant cutaneous squamous cell carcinoma. Transplantation. 2017 Apr;101(4):e133.
Renal transplantation is the best option for treatment of end stage renal disease patients, the patient received kidney transplant should be maintained on long term immunosuppressant therapy to get better results and prevent kidney loss, immunosuppressants have a lot of side effects and one of the most common side effect is high risk of malignancy.
The most common type is skin cancers about 40_50%and it’s usually more aggressive than in other population, SCC and BCC are the most common types.
Many factors that contribute in developing skin cancer like :old age,sex,smoking ,sun exposure and for those who are getting kidney transplantation using immunosuppression especially depleting agent, sensitization, acute rejection and dialysis period ,also geographical and diatery factors can contribute to develop cancers in renal transplantation patients.
Regarding skin cancers the occurance mechanism is mutation accumulation that can be recognised by the immune system, using immunosuppressant medications will affect on xeroderma pigmentosum complement group A and G .
Treatment for those patients is by using topical cream,photodynamic therapy and surgical excision, patients with repeated SCC recommended for chemoprophylaxis like retinoids and nicotinamide while to those with metastatic SCC chemo or immuno therapy recommended.
For this patient as he can be considered as low risk patient basiliximab can be used for induction with maintenance therapy on MMf ,steroid and sirolimus but if he has mismatch with the donor ATG is preferable for induction with MMF, steroid and tacrolimus with skin cancers screening and dermatological monitoring, tacrolimus can be switched to mToR inhibitors after 6moths to one year after transplantation when there is stable and good graft function .
References
Al_Adra,David.I Al_Qaoud ,Talal.(2012,March29).De Nova malignancies after kidney transplantation. CJAN,p.CJN.14570920.
Bierylo,Anna.Brzósko,Szymon. Laudańska,Elźbieta.(2017).Skin cancers in kidney transplantation recipients. Pubmed.gov.Retreivedfrom http://pubmed.ncbi.nlm.nih.gov.
In a patient with a history of skin malignancy, less aggressive immunosuppression and reduction of the dose of immunosuppressive agents when it is possible is recommended. Donor and recipient are 2 HLA mismatch. The patient has a previous history of failed transplantation. Although the patient is immunologically high risk, in the context of frequent skin cancer, induction therapy with non-depleting agents such as basiliximab may be appropriate.
Since mTOR inhibitors compared with CNIs may reduce the risk of nonmelanoma skin cancer and MMF is associated with a lower incidence of skin cancers compared with azathioprine in organ transplant recipients, the best choice for maintenance therapy in this patient may be combination of sirolimus, MMF and prednisolone.
Self-examination and examination by a physician regularly are warranted. Suspicious lesions should undergo biopsy. Avoidance of excessive sun exposure and use of sun block is recommended.
In the circumstances of 5 HLA-mismatches with HLA-B51 DSA with MFI>1000 and negative flow crossmatch, using a depleting antibody with less influence on increasing malignancy such as alemtuzumab may be appropriate.
-What is your prophylactic approach against his skin cancer?
prophylactic approach :good dermatological follow up ,avoid sun exposure and
use of sun screen .
one of the most reasons for dermatological cancers is immune suppression. shifting triple to dual or replacing CNI with mTOR inhibitors is key here. the patient has the most common two cancers seen in solid organ transplants. the failed kidney lasted 15 years. I think it was before the Tcrolimus era (supposed). taking into consideration risk of cancer and gradual chronic graft rejection, still considered as sensitized case here mismatch is 110 (ı do not know the donor: another daughter or son, cadaveric unrelated donor), the treatment will differ
as a prophyaxy against skin cancer, I will choose sirolimus/everolimus or MMF low dose plus steroid as maintatinace. Dermatologic consultation for chemoprevention measures is important
low dose rATG may be sufficeint
In the case of 212 mismatch I may prefer a triple regimen (everolimus or sirolimus plus MMF and steroid with careful monitoring against both dermatologic cancer and rejection)
induction with basiliximab as it is second transplant with 110 mismatch,
Depleting antibodies should be avoided as it favors occurrence of aggressive SCC after retransplant
maintenance therapy with tacrolimus, MMF and steroids
conversion from tacrolimus to mTORi after 4-6 months to decrease occurrence of new NMSC, mTORi decrease the recurrence of aggressive SCC
cyclosporine is associated with increased risk of SCC
Azathioprine should be avoided as increase risk of SCC
waiting period of two years if NMSC was associated with histological features of aggressiveness
strong prevention methods should be applied as the patient is old aged, with history of skin malignancy as
strict sun protection
regular dermatological monitoring for early ablation of premalignant lesions with adequate safety margins
voriconazole should be avoided as considered risk factor of NMSC
yes, it would differ as it is considered a high immunological risk transplant as 5 HLA mismatches including 2 HLA-DR, second transplant with DSA
it will need depleting induction therapy which increase the risk of recurrence of NMSC
it is better to find another donor or induction with ATG and triple maintenance therapy with conversion to mTORi after 3-4 months.
Ducroux E, Martin C, Bavinck JN, Decullier E, Brocard A, Westhuis-van Elsäcker ME, Lebbé C, Francès C, Morelon E, Legendre C, Joly P. Risk of aggressive skin cancers after kidney retransplantation in patients with previous posttransplant cutaneous squamous cell carcinomas: a retrospective study of 53 cases. Transplantation. 2017 Apr;101(4):e133.
Jiyad Z, Olsen CM, Burke MT, et al. Azathioprine and risk of skin cancer in
organ transplant recipients: systematic review and meta-analysis. Am J
Transplant. 2016;16:3490–3503.
Howard MD, Su JC, Chong AH. Skin cancer following solid organ transplantation: a review of risk factors and models of care. American journal of clinical dermatology. 2018 Aug;19(4):585-97.
Collins L, Asfour L, Stephany M, Lear JT, Stasko T. Management of non-melanoma skin cancer in transplant recipients. Clinical Oncology. 2019 Nov 1;31(11):779-88.
Suggested regimen:
-Will use IL-2I basiliximab induction but SPA should be checked first
-Maintenance IS including tacrolimus, MMF, and corticosteroids, I will not use sirolimus due to the high risk of side effects and the fact that he is already treated ofcorse before the Tx .
Prophylaxis:
-Screening, use of sun-screening, relative reduction of immunosuppression aiming at a lower target of tac trough, avoid Aza and strict follow up.
If the match was 212 with DSA (B51 with MFI 1500), but negative FCXM
-Due to 2 DR mismatch and presence of DSA, will prefer another donor as ATG will be risky here, if this is not feasible and the patient will be waitlisted for a long time ATG induction should be instituted together with triple maintenance therapy maintaining an acceptable target trough of tac , this may lead to recurrence of the patient’s skin malignancies .
What immunosuppression protocol should
be used?
induction
basiliximab
Maintenance
steroid ,mTOR inhibitors , Mycophenolate mofetil
With reduction of the dose can be considered in such patients
• What is your prophylactic approach against his skin cancer?
Pretransplant screening :
By dermatologic consultation for the screening and treatment of skin cancer and precursor lesions.
Wait time : the wait time before undergoing transplantation depends upon the tumor type and stage, presence or absence of high-risk features
Prevention :
* sun protection and skin self-examination
*Choice and modulation of immunosuppressive therapy
*Post-transplantation surveillance
• Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
negative FCXM ,positive DSA
NO need for desensitization
Induction with ATG without desensitization
Maintenance
1-steroid
2-mTOR inhibitors
3- Mycophenolate mofetil versus azathioprin
1-low mismatch,no DSA (low risk protocol)
– induction with basiliximab
-maintenance with TAC MMF steroid
-convert tac to mtor after 1st year if stable graft
2-avoid sun exposure
-screening
-convert TAC to mTOR if graft stable after 1 year as mTOR has anti prolefrative effect
3-no
DSA MFI positive but low titre
mismatch 5 mean bad one but still -ve crossmatch and low DSA
patient 71 years old with history of SCC so he is on high risk for recurrence or new malignancies so avoid heavy induction
-Renal allograft recipients have a higer risk for developing skin cancers. Renal allograft recipients required a high dose of immunosuppression drugs for a long time which impaired the immune system to destroy or repair UV-damaged cells allowing these cells to develop into cancers.
Risk factors for skin cancers:
1. immunosuppressant medication for a long time.
2. Fair skin
3. older age
4. Infection with HPV.
5. history of significant UV exposure from sun or sunbed.
6. history of skin cancers or pre-cancerous lesions before transplant.
According to KDIGO 2020 no waiting time after curative treated BCC or SCC.
This patient has mismatch 110 and FXCM negative with a history of a failed kidney transplant, so he needs screening for DSA by SAB. Induction therapy by basiliximab and then maintenance therapy with steroid, MMF, tacrolimus, and early conversion of tacrolimus to sirolimus.
Prophylactic measures against skin cancers:
1. always put on sunscreen.
2. avoid sun exposure
3. cover up all the body with long sleeves-shirt
4. self-skin examination to detect any skin lesions and to report any new lesion to a specialist.
5. Dermatological consultation monthly.
-If the patient match was 212 with DSA and negative FXCM same induction agent with basiliximab and maintenance immunotherapy Tacrolimus, MMF, Steriod and early conversion of tacrolimus to sirolimus.
References :
1.Dr Mathew Ludgate. MBChB, Dept of Dermatology Greenlane Hospital, Auckland, New Zealand, 2005. Skin cancer in transplant recipients.DermNet N-Z
2.Laura J James, Valeria Saglimbene, Germaine Wong, Allison Tong Laurence Don Wai Luu, Jonathan Craig, Kirsten Howard. Behavioural and pharmaceutical interventions for the prevention of skin cancers in solid organ transplant recipients: a systematic review of randomised controlled trials.BMJ journal.volume10 issue 5
What immunosuppression protocol should be used?
Negative XM and low mismatch so induction with Basiliximab and maintenance therapy with Tac ,MMF and steroids then after 3-6 months conversion of Tac to mTORi can be done.
What is your prophylactic approach against his skin cancer?
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
In this case higher degree of mismatching, DSA class I , still XM is negative,, I prefer to use ATG as induction and Tac, MMF and steroid for maintenance therapy for 3-6 months then to replace Tac with mTORi with monitoring of DSA level and protocol biopsy.
References:
1- What immunosuppression protocol should be used?
I will use basiliximab as induction therapy, with triple immune suppressants including MTOR I
2- What is your prophylactic approach against his skin cancer?
· Regular Skin surveillance
· Avoid exposure to the sun for long period.
3- Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
No, though he will be at high immunological risk, considering his age and his past history of skin cancer I will still go for basiliximab as induction therapy, with an MTOR I-based regimen.
What immunosuppression protocol should be used?
Cutaneous squamous cell carcinoma (SCC), basal cell carcinoma considered the comments type of malignancy in organ transplantation, skin malignancy. usually single or multiple in sun exposed area like face lip, hands ,bald scalp ,more in fair skinned recipients around 50% and < 6% in dark skin peoples predictors include history of pre transplant skin cancer , male sex ,white race , age at transplant in addition to the the direct effect of the immunosuppressive agents and proliferation of oncogenic viruses ( viral warts) ,in addition recipients with pre transplant nonmelanoma skin cancer they are at risk of post-transplant solid organ cancer or second primary cancer with in first 5 years after transplantation with increased risk of graft failure and death , patients survival reduced to < 50% in 5 years post transplantation and 10 years survival further reduced to < 20% (2).
He is old recipient 71 years with previous transplantation, whats the cuase of failed transplant? details history of BCC and SCC sites ? Locally invasive? histology type, staging ? when the surgery done? Is he cured for at least 2-5 years after complete surgical excision, what type of treatment he received, what type of induction he received in previous transplantation, history of pretransplant skin cancer? whats his regular immunosuppressive medication ,any rejection episodes since last 15 years that put him at risk of intense exposure to IS , family history of cancer, all these information with the proper assessment by oncology team will help to decide about transplantation time and proper and safe use of induction and maintenance IS IF he is in cured for minimum 2 -years then Induction with basiliximab two doses or low dose ATG not more than 4-4.5mg /kg ,followed by maintenance IS with tacrolimus and MMF avoid cyclosporine and azathioprine , DSAs monitoring proteinuria , dyslipidemia, conversion to everolimus based with CNI minimization after 3 – 6 months mTOR inhibitor, which has better efficacy in control of epithelial cell–derived skin cancers.
What is your prophylactic approach against his skin cancer?
Avoid sun exposure, use sunscreen, regular self-examination and be screened annually by a dermatologist. Though squamous cell skin cancers, if untreated, can metastasized.
Waiting time for transplant nonmelanoma Skin cancer(c-SCC) (5).
Low risk no waiting, no delay necessary
High risk Skin cancer(c-SCC),
Without neuronal invasion wait for 2 years
High risk Skin cancer(c-SCC), with neuronal invasion or more than two high risk, wait for 2-3 years
High risk with nodal mets 5 years
Systemic mets, not fit for transplantation.
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
previous transplant with more mismatch , DSAs he is high immuological risk
Induction with basiliximab or alterantive low dose ATG not more than 4.5mg / kg followed by maintenance with triple immusupression tacrolimus , MMF , steriod with early conversion to everolimus based IS in 3-6 months , , with advise for self assesment and deramatological screen , skin protection with sunscreen,viral screen and DSAs monitroing, with protienuria.
according to the results of Transform study 2018, confirm that use of everolimus with reduced-exposure CNI is noninferior to current standard of care, mycophenolic acid (MPA) and standard-exposure CNI, both with induction therapy and maintenance corticosteroids (mild to moderate immunological risk), in preventing acute rejection and preserving graft function with lower infection rate in everolimus group (5).
references:
1-Association of Pretransplant Skin Cancer with Posttransplant Malignancy, Graft Failure and Death in Kidney Transplant Recipients. Kang W, Sampaio MS, Huang E, Bunnapradist S Transplantation. 2017;101(6):1303.
2-KDIGO guideline 2020
3- Incidence of skin cancer after renal transplantation in The Netherlands
M M Hartevelt 1, J N Bavinck, A M Kootte, B J Vermeer, J P Vandenbroucke
Subsequent squamous- and basal-cell carcinomas in kidney-transplant recipients after the first 4-skin cancer: cumulative incidence and risk factors
Hermina C Wisgerhof 1, Jeroen R J Edelbroek, Johan W de Fijter, Geert W Haasnoot, Frans H J Claas, Rein Willemze, Jan N Bouwes Bavinck transplantation. 2010 May 27;89(10):1231-8.
4- Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation
Julio Pascual,corresponding author1 Stefan P. Berger,2 Oliver Witzke,3 Helio Tedesco,4 Shamkant Mulgaonkar,5 Yasir Qazi,6 Steven Chadban,7 Federico Oppenheimer,8 Claudia Sommerer,9 Rainer Oberbauer,10 Yoshihiko Watarai,11 Christophe Legendre,12 Franco Citterio,13 Mitchell Henry,14 Titte R. Srinivas,15 Wen-Lin Luo,16 AnaMaria Marti,17 Peter
Bernhardt,17 Flavio Vincenti,18 and on behalf of the TRANSFORM Investigators J Am Soc Nephrol. 2018 Jul; 29(7): 1979–1991.
5-Recommendations for Solid Organ Transplantation for Transplant Candidates With a Pretransplant Diagnosis of Cutaneous Squamous Cell Carcinoma,Merkel Cell Carcinoma and Melanoma: A Consensus Opinion From the International Transplant Skin
Cancer Collaborative (ITSCC), American Journal of Transplantation 2016; 16: 407–413.
A- What immunosuppression protocol should be used?
Induction therapy will be Basiliximab , Tacrolimus, cellcept, steroid
After stabilization of graft function m TOR replace tacrolimus
B- What is your prophylactic approach against his skin cancer:?
Avoid direct sun exposure (sunscreen/ cloths)
Regular self-examination to the skin
Dermatologist follow up regular
· Patient with history of basal cell carcinoma of the skin does not require any waiting time after successful removal of the tumor before transplantation (grade C).
· Patient with history of squamous cell carcinoma of the skin, no steady recommended about a waiting time before transplantation. (Grade C)
C- I do not know yet
Reference:
1. Knoll G, Cockfield S, Blydt-hansen T, Baran D, Kiberd B, Landsberg D. Canadian Society of Transplantation consensus guidelines on eligibility for kidney transplantation. 2005;173(10).
1- This patient is a standard risk pt ( despite it is his second transplant ) but negative FCXM and adequate HLA matching with no DSA
· Induction with basiliximab would be suitable.
· Maintainance therapy : Sirolimus + MMF and steroid ( as m TOR has antineaplastic effect and CNI inhibitors are associated with increased incidence of skin cancers)(1)
2- Prophylaxis against skin cancer :
a- Regular dermatological consultation , examination and biopsy of any suspicious skin lesions.
b- Retransplantation is scheduled after skin cancer according to the stage of the tumer and range from no waiting time for early stages up to at least 2 y from complete treatment of SCC of advanced stages.
c- Avoid prolonged sun exposure , tanning beds
d- Appling sun block, wear sun glasses.
3- Management If the match was less and low level DSA are found :
Patient in this case will be high risk , however due to previous history of skin cancer and negative FCXM as well as old age (immunesencenses) , I would prefer induction with basiliximab and maintenance with with m Tor , MMF and low dose steroid .
1- Dantal, Jacques et al. “Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results.” Journal of clinical oncology : official journal of the American Society of Clinical Oncology vol. 36,25 (2018): 2612-2620. doi:10.1200/JCO.2017.76.6691
What immunosuppression protocol should be used?
As this patient has low risk SCC and BCC , no waiting time is required.1 We can proceed for transplantation after dermatological consultation and after taking the following precautions:
· Low dose mTOR and low CNI based regimen as high doses and longer duration are associated with increased incidence of skin malignancies
· Avoid cyclosporine
· MMF can decrease the risk of SCC and can increase the risk of BCC 2
What is your prophylactic approach against his skin cancer?
· Avoid sun exposure with precautions for occurrence of vitamin D deficiency as a consequence
· Dermatological monthly follow up for detection of early recurrence of skin cancer
· Consideration of chemo protective medication as it is indicated for those who develop multiple SCCs (more than five) every year or who have aggressive SCCs or early onset of SCCs ( systemic retinoids, capecitabine, and nicotinamide.)
· Avoid voriconazole as prophylaxis and treatment of invasive fungal infections2
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
Yes because with this doner we need to have induction therapy ( second transplant with 2 DSA mismatch) which will increase the risk of skin cancer recurrence. Besides mTOR use will increase the risk of rejection and it was associated with higher rate of mortality3 . I prefer to look for another doner if possible.
1-Zwald F, Leitenberger J, Zeitouni N, Soon S, Brewer J, Arron S, Bordeaux J, Chung C, Abdelmalek M, Billingsley E, Vidimos A, Stasko T. Recommendations for Solid Organ Transplantation for Transplant Candidates With a Pretransplant Diagnosis of Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma and Melanoma: A Consensus Opinion From the International Transplant Skin Cancer Collaborative (ITSCC). Am J Transplant. 2016 Feb;16(2):407-13. doi: 10.1111/ajt.13593. Epub 2016 Jan 28. PMID: 26820755.
2-Mittal, A., & Colegio, O. R. (2017). Skin Cancers in Organ Transplant Recipients. American Journal of Transplantation, 17(10), 2509–2530. doi:10.1111/ajt.14382
3. Knoll G A, Kokolo M B, Mallick R, Beck A, Buenaventura C D, Ducharme R et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data BMJ 2014; 349 :g6679 doi:10.1136/bmj.g6679
good reply. Would you like to know how long ago were the SCC & BCC excised?
thank you sir
for BCC we do not wait but for SCC we need to wait for 2 years
skin cancer is long term complications of long term graft survivors.
M M Hartevelt 1, J N Bavinck, A M Kootte, B J Vermeer, J P Vandenbroucke. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation.1990 Mar;49(3):506-9.
immunosuppression protocol is basiliximab which carries less risk of cancer development, tacrolimus, MMF and steroid are maintenance therapy.
prophylactic approach against skin cancer:
1- regular dermatological consultation and follow up.
2- avoid any risk factors like sun exposure for longtime, protect with sunscreen, sunglass, avoid residence in high altitude which expose to more sunlight
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
no. will not be differ, i know that the mismatch increased but i will use basiliximab as induction, and tacrolimus , MMF and steroid as a conventional , with follow up of DSA.
old age recipient has lower risk of rejection than younger age so use of basiliximab even with 212 mismatch can be safe
being old age and with history of skin cancer will carry more risk of malignancy , this also will support use of basiliximab as induction
Any role for motor inhibitors in your maintenance protocol?
The recipient is an elderly male, with history of prior failed transplant and 0 DR mismatch.
I would use Induction Basiliximab in the patient with maintenance immunosuppression in form of Tacrolimus, MMF and steroids.
Tacrolimus can be substituted with mTOR inhibitors after 3 to 6 months if GFR>40 and proteinuria less than 800 mg/day
Dermatological consultation is important prior to transplant.
Waiting period post SCC depends on the type of SCC and rages from nil waiting time (for low-risk) to 2-5 years (for high risk: >2 cm, > 2 mm deep, at ear, lip, scalp and temple, poorly differentiated, perineural invasion and history of recurrence, nodal spread). In metastatic lesions, transplant should be avoided. (1)
Once the patient is transplanted, regular self-examination by the patient should be advised. Skin examination at every clinic visit is a good practice. Patient should be encouraged to avoid sun, use sunscreen, cover-up wth clothes, sunglasses, headgear to avoid direct sun-exposure.
Transplanting this donor kidney with 212 mismatch, the risk would be high and it is prudent to use ATG as induction. No desensitization as FCXM is negative. Maintenance immunosuppression with Tacrolimus, MMF and steroids. mTOR inhibitors can be introduced after 3 to 6 months.
Post transplant DSA monitoring, Protocol biopsy, in addition to skin examination at regular intervals.
Reference:
1)Zwald F, Leitenberger J, Zeitouni N, et al. Recommendations for Solid Organ Transplantation for Transplant Candidates With a Pretransplant Diagnosis of Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma and Melanoma: A Consensus Opinion From the International Transplant Skin Cancer Collaborative (ITSCC). Am J Transplant 2016;16:407-413.
good reply
Non-melanoma skin cancer occurs more frequently in renal transplant recipients than in
the general population.
Several risk factors are recognized including fair complexion, high sun-exposure, and
greater age at first transplant.
Use of mTORi (Sirolimus) instead of CNI protocol has been shown to reduce risk of new
squamous cell cancer in patients with a prior history of skin cancer .
Induction therapy with monoclonal and polyclonal antibodies renal transplant recipients
is not associated with an increased risk of NMSC, so ATG can be used in this high risk
patient
Screening/Education for prevention:
Evaluated before transplantation for factors that may increase their risk of skin cancer.
Minimizing immunosuppression.
Should also receive detailed education regarding sun protection (use of sunscreen, hats,
avoidance of exposure to ultraviolet radiation during sun peak hours) should be
employed.
How to perform self-examinations.
Should be advised of the importance of frequent follow-up full skin examinations by a
dermatologist. Follow-up examinations should occur anywhere from every 3 months to
every 24 months, depend risk factors.
RiskFactors Followup
Only risk factor immunosuppression. 12-24mo
Risk factors, such as sun exposure or fair skin, but no history of AK no
NMSC .
Every 6-12 mo.
Early cutaneous carcinogenesis, ie, AKs or warts or 1-4
NMSCs/yr. Every 3-6 mo.
Moderate cutaneous carcinogenesis, ie, 5-10 NMSCs/yr, high-risk SCC,
MCC, or MM
Every 3 mo.
Severe cutaneous carcinogenesis, ie, >10 NMSCs/yr, metastatic skin
cancer Every1-3 mo.
References:
1-Meena K. Singh, MD,* and Jerry D. Brewer, MD et al. Current Approaches to Skin
Cancer Management in Organ Transplant Recipients. Semin Cutan Med Surg 30:35-47 ©
2011.
2- Mona D. Doshi . Cancer in Solid Organ Transplantation, MD Department of Medicine,
Wayne State University, Detroit, Michigan.
3- J. Bernat-García etal The Role of New Immunosuppressive Drugs in Nonmelanoma
Skin Cancer in Renal Transplant Recipients. DOI: 10.1016/j.adengl.2014.06.005.
why would surgeons not use sirolimus immediate post surgery?
Sirolimus has been shown to be associated with poor wound healing, hence not preferred to be used in immediate post-operative period by surgeons
-Transplantation should not be contemplated until the malignancy has been successfully treated, and a suitable disease-free interval achieved.
Therefore most guidelines recommend that patients should wait for at least 2 years and in some cases up to 5 years after successful cancer treatment except patients with non-melanoma skin cancer.
the EDTA guidelines suggest that for each patient decision should be individualised as increasing age and male gender are associated with an increased risk of any de novo cancer specially non-melanoma skin cancer
For induction Thymoglobulin carried a higher relative risk to increase PLTD than Fresenius ATG
meanwhile IL-2 R inhibitor has no consistent evidence to increase malignancy risk so it can be used as patient has 110 mismatch and negative FXCM with history of 7BCC and 2 early SCC
For maintenance
MMF /CNI /Glucocorticoids then CNI can be substituted with mTOR
Glucocorticoids have been, indeed, proposed to play a dual role in oncogenesis: a direct pro-oncogenic effect in lymphoid cells and an indirect effect on the ability of cancer cells to escape immunosurveillance.
MMF showed in vitro to exert an anti-proliferative effect in variable cancer cell lines
Data the Scientific Registry of Transplant Recipients (SRTR), however, suggest that MMF use in kidney graft recipients is associated with a reduced risk of any cancer and, in particular, of PTLD
CNI promotes the development and progression of neoplastic diseases including transforming growth factor β1 production and suppression of anti-tumour-specific immune responses
The results of several clinical trials demonstrated that mTOR inhibition can induce a significant stabilization of progressive neoplastic diseases and even tumour regressions
Multiple studies concluded that maintenance of mTOR inhibitors-based immunosuppression is characterized by a significantly reduced risk to develop any de novo post-transplant malignancy or non-skin solid malignancy compared to CNI based immunosuppressive regimen
Multiple studies mentioned the regression of this neoplastic disease after CNI withdrawal and introduction of mTOR inhibitors.
Others recommended that since the association of mTOR inhibitors with CNI has been shown to achieve a significant reduction in the incidence of post-transplant malignancies, this immunosuppressive regimen may represent a valuable option to prevent neoplastic disease specially , for transplant recipients with a concomitant high immunologic risk.
-Prevention of post-transplant malignancies is the main cocern in the follow-up of transplant recipients
Cancer screening Monthly by self-skin examination, total body skin examination every 12 months by expert physicians and dermatologists
patients at higher risk those with certain ethnicity, geographic area of residence or serologic positivity for HHV, History of skin cancers or pre-cancerous lesions before the transplant ,Fair skin and significant UV exposure from sun so they may benefit from more frequent screening.
Reduction or cessation of immunosuppressive therapy is useful primarily in patients who had a renal transplant since the loss of the graft to rejection is not a fatal event in these patients specially CNI
Prophylactic measures also include
Applying sunscreen , wearing sunglasses and avoid direct exposure to the sun as well as to cover up well and wear hats when being outdoor
– If the match was 212 with DSA (B51 with MFI 1500), but negative FCXM
The management will differ as induction will be by Fersenius ATG
And maintenance by MMF /CNI /m TOR along with steroids with close monitoring
References
-Stallone G etal. Management and prevention of post-transplant malignancies in kidney transplant recipientsClinical Kidney Journal, 2015, vol. 8, no. 5, 637–644
-Ludgate M etal .Skin cancer in transplant recipients. DermNet NZ all about the skin 2005
This patient as per case scenario has properly excised non melanoma skin neoplasms. How long would you wait prior to transplant. Please quote the guideline, you answer from
the patient has 2 antigen mismatches out of 6 with no DSA and FCXM is negative(he is low immunological risk).but he is old age with his h\o of skin cancer(he is risky for malignancy), so induction with Basiliximab, and maintenance first 3-month with tacrolimus.after 3 months can be shifted to mTOR(if proteinuria <800mg and GFR> 40ml\min and no rejection episode).
Dermatologic follow-up for skin cancer screening pretransplantation and posttransplantation and education regarding sun protection are imperative for those with a history of SCC because there is an increased risk of developing subsequent skin cancers, ranging from 40% to 80% in renal transplant patients.
-Prophylactic against skin cancer
the patient has positive DSA and negative FCXM: better for induction ATG, but low dose total < 4mg\kg ).and maintenance on (mTOR with a level around 3 and tacrolimus around 7 first 3 months) and reverse the ratio after the first 3 months.(transform study3).
1-Ismail F, Michell L, Casebonne D, et al. Specialist dermatology clinics for organ transplant recipients significantly improve compliance with photoprotection and levels of skin cancer awareness. Br J Dermatol 2006; 155: 916– 925.
2-Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: Part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011.
3-J Am Soc Nephrol. 2018 Jul; 29(7): 1979–1991.
Published online 2018 May 11. DOI: 10.1681/ASN.2018010009
Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation
very good
The using of immunosuppression(IS) is vital for graft survival but it is not danger free. Long-term IS is associated with increased risk of NMSC(SCC, BCC). Risk of BCC increase around 10-16 times in SOT, while SCC risk increase 65-250 fold( BCC:SCC is 1:4 in renal transplant recipients). Risk factors for NMSC include:
The incidence of NMSC in organ transplant recipient is high, & the mortality & morbidity increased with multiple & aggressive behavior of tumor. CsA classifies as carcinogenic by International Agency for Research on Cancer. Also Tac was associated with increased risk of skin tumor but to a lesser extent the CsA. It was found that patients with history of skin cancer had 30-70% chance to have another skin cancer. Switching to mTOR-I within 3 months post transplantation was associated with decreased risk of NMSC( without risk of graft loss) when compared to CNI based regime. This effect of mTOR-I persist if used in combination with CNI.
Our patient had high recurrence of NMSC so he will benefit from switching to mTOR-I regime. Prophylactic measures include:
The recipient HLA mismatch is high, it is better to find more suitable donor. His DSA is <2000 MFI so none for desensitization, but if there is no other donor, the patient should receive ATG for induction with maintenance IS mTOR-I +CNI + MMF with steroid & close monitoring of DSA.
References:
gender is sex type
white, black skin colour (ethnicity)otherwise
conise and good though better to mention each question seperatly.
Thank you, I meant race not gender
What immunosuppressant protocol should be used?
This patient immunological risk is high (his previous transplant) despite his 2 HLA mismatch and negative FCMX in the absence of DSA .At the same time his skin cancer , is another concern regarding re transplant .
This patient needs induction ,it is better to use interleukin-2receptor antibodies ,which do not confer an additional malignancy risk . The new protocols ( use belatacept or steroid free regimen) showed long term beneficial effect on tumor recurrence ,can hopefully be used in the future . In maintenance protocol we can use MTOR inhibitor ,which seem to be advantageous for non-melanoma skin cancer .it is better to avoid azathioprine ,it is associated with increased risk of skin cancer .
What is your prophylactic approach against his skin cancer?
A careful history of previous skin cancer should also be obtained to determine the appropriate follow-up frequency or the wait time before proceeding to transplantation .
Transplant candidates and potential donors should be screened for cancer as part of the assessment process.
Post-transplantation cancer screening needs to be tailored to the individual patient, considering the cancer risk of the individual, co morbidities, overall prognosis and the screening preferences of the patient. In kidney transplant recipients diagnosed with cancer, treatment includes conventional approaches, such as radiotherapy and chemotherapy, together with consideration of altering immunosuppression.
A dermatological consultation is recommended before transplantation for the screening and treatment of skin cancer and precursor lesions.
Transplant candidates with extensive field disease (ie, multiple actinic keratoses, disseminated porokeratosis) but without a history of skin cancer may proceed to transplantation, with the recommendations that all field disease be appropriately managed by the dermatologist.
For patients with a history of prior cutaneous malignancy, the wait time before undergoing transplantation depends upon the tumor type and stage, presence or absence of high-risk features, and availability of a management approach alternative to transplantation.
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
Yes
HLA B51 is a tumor suppressor gene .it is better to reverse the effect of DSA targeting this gene ,which require rapid elimination of antibody-secreting plasma cells with a proteasome inhibitor (bortezomib) followed by sustained inhibition of of plasma cell with belatacept
Reference;
u E, Wong G, Chapman JR. Cancer in kidney transplant recipients. Nat
Rev Nephrol 2018; 14: 508–520
de Fijter JW. Cancer and mTOR inhibitors in transplant recipients.
Transplantation 2017; 101: 45–55
Kang W, Sampaio MS, Huang E, Bunnapradist S. Association of Pretransplant Skin Cancer With Posttransplant Malignancy, Graft Failure and Death in Kidney Transplant Recipients. Transplantation 2017; 101:1303.
Reversing donor-specific antibody responses and antibody-mediated rejection with bortezomib and belatacept in mice and kidney transplant recipients First published: 03 April 2020
https://doi.org/10.1111/ajt.15881
good you noticed that the DSA mentioned is specified as B51 with MFI 1500
being a split antigen of B5
what is the significance you need to justify your explanation
please revise your last paragraph for drug action
thanks prof
it is true ,no evidence to use bortezomib to reverse the effect HLA B51 DSA in human .
Melanoma is found to be associated with Ag epitopes presented in other HLA contexts, such as A2, A1, B51, and Cw3.
Identification of Five New HLA-B*3501-Restricted Epitopes Derived from Common Melanoma-Associated Antigens, Spontaneously Recognized by Tumor-Infiltrating Lymphocytes Houssem Benlalam, Boris Linard, Yannik Guilloux, Agnès Moreau-Aubry, Laurent Derré, Elisabeth Diez, Brigitte Dreno, Francine Jotereau and Nathalie Labarrière
J Immunol December 1, 2003, 171 (11) 6283-6289; DOI: https://doi.org/10.4049/jimmunol.171.11.6283
What immunosuppression protocol should be used?
In this patient with history of multiple skin malignancies BCC and SCC, dermatological consultation is recommended. For this patient with early SCC no waiting time is required after excision, so we can proceed with transplantation without delay. In contrary, if high risk SCC is diagnosed, then 2-3 years waiting time after excision is required. For BCC no waiting time is required after excision.
The risk of post-transplant skin malignancy is influenced by the choice of the immunosuppression. Regimens including mTORi rather than CNI may reduce the risk for skin cancer. One study reported that sirolimus was associated with a 40 percent reduction in the risk of malignancy and nonmelanoma skin cancer. Another study demonstrated that sirolimus was associated with a 51 percent reduction in the incidence of nonmelanoma skin cancer.
What is your prophylactic approach against his skin cancer?
The risk of SCC in organ transplant recipients is 60 to 250 times higher than general population. SCC in SOT may be aggressive and associated with a higher mortality rate than in the general population.
Patients should be educated about the importance of sun avoidance, sun protection, sunscreens and the recognition of the early signs of cutaneous malignancies.
Chemopreventive measures can also be considered for patients who develop multiple SCCs per year, aggressive SCCs, or accelerated development. Chemoprotective strategies include acitretin, nicotinamide, capecitabine, and photodynamic therapy.
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
If the match is 212, the risk of rejection is high, and the use of m-TORi based maintenance immunosuppression would be out of evidence.
Induction therapy should be with r-ATG without desensitization as the flowcytometry crossmatch is negative. I would suggest maintenance therapy with low dose CNI/ everolimus /MMF/steroids. This combination has been shown to be noninferior in terms of immunosuppression but with better outcomes in terms of skin cancer occurrence and recurrence.
References
-UpToDate
-Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data. BMJ 2014; 349:g6679.
-Yanik EL, Siddiqui K, Engels EA. Sirolimus effects on cancer incidence after kidney transplantation: a meta-analysis. Cancer Med 2015; 4:1448.
-Dantal J, Morelon E, Rostaing L, et al. Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results. J Clin Oncol 2018; 36:2612.
-Pascual J, Diekmann F, Fernández-Rivera C, Gómez-Marqués G, Gutiérrez-Dalmau A, Pérez-Sáez MJ, et al. Recommendations for the use of everolimus in de novo kidney transplantation: False beliefs, myths and realities. Nefrologia. 2017;37:253–266.
Wise decision for using ATG for induction and no desensitisation
wouldthis be better than Basiliximab same maintenance with close monitoring
Thank you Dr for your reply. In the settings of high risk for rejection there is no doubt that rATG is superior to Basiliximab in terms of immunosuppression which is required in this scenario. But the risk of infections and malignancy is higher.
So we need to weigh the risks and benefits of both regimens, as the risk for rejection is acceptable if and only if it is overweighed by a great benefit, in this case cancer prevention.
So the major question is which is more risky? risk of rejection OR risk of skin cancer? For this question I need to review some evidence.
What immunosuppression protocol should be used?
What is your prophylactic approach against his skin cancer?
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
Referrences
1-Euvrard S, Morelon E, Rostaing L, et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N Engl J Med 2012; 367: 329–339.
2-Jiyad Z, Olsen CM, Burke MT, Isbel NM, Green AC. Azathioprine and Risk of Skin Cancer in Organ Transplant Recipients: Systematic Review and Meta-Analysis. Am J Transplant. 2016 Dec;16(12):3490-3503. doi: 10.1111/ajt.13863. Epub 2016 Jul 7. PMID: 27163483.
What about waiting time before transplantation in a treated and cleared skin cancer.
sugested IS protocols evaluation for such a case
1/ Is protocol should contain low dose mTOR inhibitors and low dose CNIs.
2/ Consideration of wait time before transplantation :
SCC:
BCC-MCC:
Reference:
1.Recommendations for Solid Organ Transplantation for Transplant Candidates With a Pretransplant Diagnosis of Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma and Melanoma: A Consensus Opinion From the International Transplant Skin Cancer Collaborative (ITSCC)https://doi.org/10.1111/ajt.13593
thankyou
Cutaneous malignancy is the most common malignancy encountered in renal transplantation (1) and constitute around 40% of malignancies in renal transplant recipients, and are 7 fold higher in renal transplant recipients when compared to general population (2)
90% of cutaneous malignancies are due to SCC and BCC (3), others include melanoma, Kaposi sarcoma, and Merkel cell carcinoma.
In renal transplantation, SCC occur more commonly than BCC (although in the general population BCC is more common)
Risk factors or developing BCC, SCC
A- Factor related to transplantation
B- Patient factors including
Prevention and management of skin cancer in transplant recipients
A- Screening
B- Wait time before transplantation (7)
C- Use of sunscreen
D- Reduction of immunosuppression
E- Modification of immunosuppression
F- Chemoprevention for SCC
G- Treatment is as that of the general population
Prognosis
What immunosuppression protocol should be used?
What is your prophylactic approach against his skin cancer?
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
REFERENCES
1. Mittal A, Colegio OR. Skin Cancers in Organ Transplant Recipients. Am J Transplant 2017; 17:2509.
2. Park CK, Fung K, Austin PC, et al. Incidence and Risk Factors of Keratinocyte Carcinoma After First Solid Organ Transplant in Ontario, Canada. JAMA Dermatol 2019; 155:1041.
3. Chockalingam R, Downing C, Tyring SK. Cutaneous Squamous Cell Carcinomas in Organ Transplant Recipients. J Clin Med 2015; 4:1229.
4. Kuschal C, Thoms KM, Boeckmann L, et al. Cyclosporin A inhibits nucleotide excision repair via downregulation of the xeroderma pigmentosum group A and G proteins, which is mediated by calcineurin inhibition. Exp Dermatol 2011; 20:795.
5. Ramsay HM, Fryer AA, Hawley CM, et al. Non-melanoma skin cancer risk in the Queensland renal transplant population. Br J Dermatol 2002; 147:950.
6. Brewer JD, Colegio OR, Phillips PK, et al. Incidence of and risk factors for skin cancer after heart transplant. Arch Dermatol 2009; 145:1391.
7. Zwald F, Leitenberger J, Zeitouni N, et al. Recommendations for Solid Organ Transplantation for Transplant Candidates With a Pretransplant Diagnosis of Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma and Melanoma: A Consensus Opinion From the International Transplant Skin Cancer Collaborative (ITSCC). Am J Transplant 2016; 16:407.
8. Préterre J, Visentin J, Saint Cricq M, et al. Comparison of two strategies based on mammalian target of rapamycin inhibitors in secondary prevention of non-melanoma skin cancer after kidney transplantation, a pilot study. Clin Transplant 2021; 35:e14207.
9. www.cdc.gov/cancer/skin/statistics/race.htm (Accessed on August 22, 2016).
Exellant Sherif
last option is prudent and waiting time is OK(thankyou for mentioning WAITING TIME.
post cure.
What immunosuppression protocol should be used?
What is your prophylactic approach against his skin cancer?
A-FOR INDUCTION IMMUNOSUPRRSEION ,
i will go for basilixmab low immunlogical risk pt
B-MAINTINACE IMMUNOSUPPRESION.
i will go for mtor inhibtors (sirolumus ,mmf with ,steroids ) as maintinace after 1-3 month far from transplantion to decreas the risk of skin cancer again.in the fisrt one to three month i will start the (cni, mmf , pred)
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
no it will not change anything in both induction immunsprresion
or maintinace but , close mointoring of patient kidney panel with dsa and protocol biobises may be offered to insure that the graft is ok and no underlying rejection could be missed.
reffernce
NCT00133887, EUDRACT 2005-004509-27
accepted last decision ( he is 65 getting aLD and 15 years after cure
precautions have to be discussed with the patient.
What immunosuppression protocol should be used?
Since DSA negative, FCXM negative with prior history of skin cancer
Plan would be –
Induction with basiliximab
Maintenance – Tacrolimus, MMF, Prednisolone
At 1 year if no episodes of rejection ,DSA negative ,Egfr >45,UPCR<500 will start Sirolimus at loading dose of 6mg and 24 hrs later maintenance dose of 4mg OD. Increase MMF to 1gm BD .check sirolimus level after 7 days and if levels between 5-10ng/ml taper tacrolimus by 50% and taper and omit 3 days later and continue maintenance with Sirolimus, MMF, Prednisolone .
What is your prophylactic approach against his skin cancer?
Avoid exposure to sun
Apply sun screen
Self examination daily
Dermatology visit every 3 months.
Would your management differ if the match was 212 with DSA (B51 with MFI 1500), but negative FCXM?
Induction with ATG
Maintenance – Tacrolimus, MMF, Prednisolone
At 1 year if no episodes of rejection ,DSA negative ,Egfr >45,UPCR<500 will start Sirolimus at loading dose of 6mg and 24 hrs later maintenance dose of 4mg OD. Increase MMF to 1gm BD. check sirolimus level after 7 days and if levels between 5-10ng/ml taper tacrolimus by 50% and taper and omit 3 days later and continue maintenance with Sirolimus, MMF, Prednisolone